Effects of Chronic Arsenic Exposure on Hematopoietic Function in Adult Mammalian Liver

Abstract

In these studies the effects of ingested arsenic (As+15) on hepatic heme biosynthetic capability and hemoprotein function in adult male rats were investigated. Animals exposed for 6 weeks to 0, 20, 40, or 85 ppm sodium arsenate in the drinking water suffered depression of hepatic 8-aminolevulinic acid (ALA) synthetase and heme synthetase (ferrochelatase) activities, with maximal decreases to 67 and 55% of control levels, respectively, at 85 ppm. Concomitantly, urinary uroporphyrin levels were elevated by as much as 12 times, and coproporphyrin by as much as 9 times, control values. The rate of incorporation of 3H-ALA into mitochondrial and microsomal hemes was depressed by 40-50%o at 20 ppm but was increased with regard to controls by as much as 150%o at the higher treatment levels. A similar biphasic pattern was observed in regard to "4C-leucine incorporation into cellular membranal proteins. In contrast, the levels of ALA dehydratase, uroporphyrinogen I synthetase, aminopyrine demethylase, and cytochrome P-450 were not significantly changed in As+5-treated rats. These results support the hypothesis that chronic, low level, arsenic exposure results in selective inhibition of mitochondrial-bound heme biosynthetic pathway enzymes (ALA synthetase and heme synthetase) resulting in a substantial increase in urinary porphyrins, uniquely characterized by a greater increase in uroporphyrin than coproporphyrin levels. These changes occur independent of, or prior to, alterations in hepatic hemoprotein-dependent functions and may thus serve in the clinical analysis of pretoxic exposure to arsenic compounds in human populations.

Interactions among lead, cadmium, and arsenic in relation to porphyrin excretion patterns.

“…Cadmium by itself did not markedly alter urinary excretion of any of the measured porphyrins. Arsenic in either the organic or inorganic form produced no change in ALA excretion but caused marked increases in urinary uroporphyrin and to a lesser degree coproporphyrin, thus confirming earlier findings (4). The combination of lead plus arsenic produced an additive effect on coproporphyrin excretion but no alteration on the arsenic effect on uroporphyrin excretion indicating that the latter effect is rather specific.…”

General subcellular effects of lead, mercury, cadmium, and arsenic.

“…Mitochondria from these animals also showed 50-70% increases in the specific activities of the mitochondrial marker enzymes monoamine oxidase, cytochrome oxidase and Mg+2ATPase. Another effect involved perturbation of mitochondrial heme biosynthesis with a resulting porphyrinuria (39) which is distinct from that observed with methylmercury or lead. A maximal decrease of heme synthetase activity to 63% of control levels was observed at the 3.5 mg/kg dose level with a resultant increase in urinary uroporphyrin and a lesser increase in coproporphyrin.…”

Ultrastructural and biochemical effects of prolonged oral arsenic exposure on liver mitochondria of rats

“…In situ morphological findings were related to changes in respiratory function and the activities of marker enzymes localized in different mitochondrial compartments. Other studies dealing with the inhibitory effects of arsenate exposure on pyruvate dehydrogenase activity (12) and heme biosynthetic pathway (13) are presented in other papers.…”

“…The Other studies which relate the ultrastructural damage observed in this report to perturbation of mitochondrial heme biosynthetic pathway enzymes and subsequent porphyrinuria are described in an adjacent paper (13). Current research efforts are focussed on relating arsenate-induced changes in mitochondrial membrane structure to ion and substrate transport capability.…”